Barbiturates inhibit ATP‐K+ channels and voltage‐activated currents in CRI‐G1 insulin‐secreting cells

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Abstract
Patch‐clamp recording techniques were used to examine the effects of barbiturates upon the ATP‐K+ channel, and voltage‐activated channels present in the plasma membrane of CRI‐G1 insulin‐secreting cells. Thiopentone inhibited ATP‐K+ channel activity when applied to cell‐attached patches or the intracellular or extracellular surface of cell‐free patches. Secobarbitone and pentobarbitone were also effective inhibitors of ATP‐K+ channels in cell‐free patches, whereas phenobarbitone was ineffective. The diabetogenic agent, alloxan, which is structurally related to the barbiturates also produced an inhibition of ATP‐K+ channel activity in outside‐out patches. Whole‐cell ATP‐K+ currents were used to quantify the effects of the barbiturates: concentration‐inhibition curves for thiopentone, secobarbitone and pentobarbitone resulted in IC50 values of 62, 250 and 360 μm respectively. Phenobarbitone at a concentration of 1 mm was virtually ineffective. Calculation of the apparent membrane concentrations for these drugs indicate that for a given degree of ATP‐K+ channel inhibition a similar concentration of each barbiturate is present in the membrane. This suggests that hydrophobicity plays a primary role in their mechanism of action. The pH‐dependence and additive nature of barbiturate block also indicates a membrane site of action. Thiopentone, (100 μm) was also found to inhibit differentially voltage‐activated whole‐cell currents. The relative potency of thiopentone at this concentration was 0.64, 0.38 and 0.12 for inhibiting Ca2+, K+ and Na+ currents respectively when compared with its ability to inhibit the ATP‐K+ channel.